1. Field of the Invention
This invention is in the field of organic chemistry. More particularly, it relates to methods for the synthesis of oxygen-containing heterocyclic organic compounds, materials formed by these methods, and intermediates generated in the methods. In one application, this method is used to prepare analogs of the antimalarial agent known as qinghaosu ("QHS") or artemisinin.
2. Description of Related Art
The three prior applications noted above all related generally to the same project which is dealt with herein. The present application covers recent advances over the work covered by these earlier applications.
This invention relies on ozonolysis of vinylsilanes to give rise to polyoxaheterocyclic compounds. A reference of which we are aware which involves ozonolysis of a vinylsilane is that of George Buchi et al., Journal of the American Chemical Society, Vol 100, 294 (1978). Another reference of interest is by R. Ireland et al., Journal of the American Chemical Society, Vol 106:3668, (1984), which relates to silylation.
We also call to the Examiner's attention the publications of some of this related work appearing at M. Avery et al., Tet Lett, Vol 28:(40), 4629, (1987).
Other art of interest to the present invention relates to the ancient antimalarial natural product known as qinghaosu. The antimalarial qinghaosu has been used in China in the form of crude plant products since at least 168 B.C. Over the last twenty years, there has been an extensive interest in this material. This has led to an elucidation of its structure as ##STR2## The chemical name artemisinin has been applied to the material. This name will be used in this application to identify the material.
The carbons in the artemisinin structure have been numbered as set forth above. When reference is made to a particular location in a compound of this general type, it will, whenever possible, be based on the numbering system noted in this structure. For example, the carbon atoms bridged by the peroxide bridge will always be identified as the "4" and "6" carbons, irrespective of the fact that this invention can involve materials having different bridge-length structures in which these carbons would otherwise be properly numbered.
References to artemisinin and to certain of its derivatives include the May 31, 1985 review article by Daniel L. Klayman appearing in Science, Vol 228, 1049 (1985); and the article appearing in the Chinese Medial Journal, Vol 92, No. 12, 811 (1979). Two syntheses of artemisinin have been reported in the literature by Wei-Shan Zhou, Pure and Applied Chemistry, Vol 58(5), 817 (1986); and by G. Shmid et al. Journal of the American Chemical Society, Vol 105, 624 (1983). Neither of these synthese employs ozonolysis or the unsaturated bicyclic ketones as set forth herein.
In this specification we will at times refer to the following journal articles by way of the following footnotes: